BACKGROUND OF THE INVENTION:
Substituted pyridines are essential chemical intermediates used for the preparation of
pharmaceuticals and agrochemicals. In particular, 2,3-dichloropyridine is used as a starting
material for the synthesis of widely applied insecticides such as Chlorantraniliprole
15 (Rynaxypyr) and Cyantraniliprole (Cyazypyr).
There are several methods known in the literature for the synthesis of substituted pyridines.
Early reports by Baldwin et al., in J. Org. Chem., 1978, 43I, 2529-2535, US4279913 and
Bioorganic & Medicinal Chemistry Letters, 19(12), 3199-3203, have described the synthesis
of a variety of substituted pyridines. The condensation of alkylidene malononitrile or
20 alkylidene cyanoacetate with either triethyl orthoformate or dimethylformamide diacetal
results in the formation of equivalents of α,β,γ-unsaturated aldehydes, which undergo
cyclization with acids to provide substituted pyridines.
The preparation of 2-halogeno-3-alkylsulfonylpyridines, that involves reacting N,Ndimethylacrylaldehyde with (methylsulfonyl)acetonitrile followed by reaction with HCl gas,
25 has been reported in CN106866514.
J. Org. Chem., 1995, 60(12), 3750-3758, describes the synthesis of phenyl substituted 2-halo
pyridine compounds. Vinylogous enamino nitriles are synthesized using tertbutoxybis(dimethylamino)methane which is not suitable for large scale syntheses.
Several prior arts were able to achieve the synthesis of the vinylogous enamino
30 (malono)nitriles from alkylidene (malono)nitrile/cyanoacetates/cyanosulfonyls derivatives
3
which were easily transformed into the desired 2-halopyridine derivatives after sequential
reactions. Even though much progress has been achieved, electron withdrawing (EWG)
groups were crucial to obtain the requisite precursors for designated cyclizations in
previously described methods.
5 Further, WO2012122746, CN109280026A and CN105399663A disclose a process for the
preparation of a 2-halo substituted pyridine from a substituted pyridine via functional group
transformation, e.g. by diazotisation reaction or by using a metal catalyst like palladium
which is not economical for large scale preparations.
The use of substituted pyridines as the starting materials for the synthesis of 2,3-
10 dihalopyridines is an expensive practice. Furthermore the use of various metal catalysts leads
to the increase of steps like purification and recycling of the catalyst.
Therefore, there is a need for a process of preparation of substituted pyridines which is
simple, cost-efficientand feasible on an industrial scale.

WE CLAIM:
1. A process for the preparation of a substituted pyridine of formula (I) or a salt thereof,
wherein,
R
1 5 is selected from the group consisting of halogens and C1-C4 alkoxy;
R
2 is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C7
cycloalkyl, C1-C3 haloalkyl, heterocyclyl, O-R’, haloalkyl and O-C(O)R’;
R
3 is selected from the group consisting of hydrogen, halogen C1-C4 alkyl, C3-C7
cycloalkyl, C1-C3 haloalkyl and C1-3 alkoxy;
R
4 10 is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C7
cycloalkyl, C1-C3 haloalkyl, heterocyclyl, O-R’, haloalkyl, O-C(O)R’ and CHO;
R’ is selected from the group consisting of C1-C6-alkyl and C1-C3 haloalkyl;
or
R
2
and R3
or R3
and R4
can form a 5-6 membered carbocyclic or heterocyclic ring
15 system, which is optionally substituted by halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-
C6-alkoxy;
R
2
, R3
and R4
groups are optionally substituted with halogen, CN, C1-C6-alkyl, C1-C6-
haloalkyl, C1-C6-alkoxy;
comprising the steps of:
20 a) cyclizing a vinylogous nitrile of formula (II) or a salt thereof, by reacting with an acid
(reagent-1) and optionally in the presence of a solvent; according to the reaction
scheme-1 as depicted below:
Scheme-1
;
wherein LG represents OR’ or N(R’)2; R’, R1
, R2
, R3
and R4
25 are as defined above;
36
b) the vinylogous nitrile of formula (II) or a salt thereof, is obtained by reacting an α,βunsaturated nitrile of formula (III) or a salt thereof, with reagent-2, and optionally in
the presence of a catalyst and a solvent. according to the reaction scheme-2 as
depicted below:
5 Scheme-2:
;
wherein R2
, R3
and R4
are as defined above;
2. The process according to claim 1, wherein the reagent-1 is an inorganic acid selected
from hydrogen fluoride, hydrogen chloride or hydrogen bromide; a Lewis acid
10 selected from titanium tetrachloride, boron trifluoride etherate, copper chloride,
aluminium trichloride and zinc chloride.
3. The process according to claim 1, wherein reagent-2 is selected from:
i. a compound of formula (R5
)2NCH(OR5
)2 or a salt thereof,
ii. a compound of formula (R5
)2NCHO or a salt thereof and co-reagent (C-1),
iii. an amine of formula NH(R5
15 )2 or a salt thereof, a suitable ortho ester of
formula CR7
(OR5
)3 or a salt thereof and a co-reagent (C-2),
iv. an ortho ester of formula CR7
(R6
)3 or a salt thereof and a co-reagent (C-3),
v. a formic acid/ester of formula HCOOR7
or a salt thereof and a co-reagent
(C-4),
vi. an amine of formula N(R5
20 )3 or a salt thereof and a co-reagent (C-5),
vii. carbon monoxide and a co-reagent (C-4).
4. The process according to claim 1, wherein reagent-2 is selected from a compound of
formula (R5
)2NCH(OR5
)2 or compound of formula (R5
)2NCHO or a salt thereof and
co-reagent (C-1), or a salt thereof.
25 5. The process according to claim 1, wherein the solvent is selected from aliphatic,
alicyclic or aromatic halogenated hydrocarbons such as chlorobenzene,
dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or
trichloroethane; ethers such as diethylether, diisopropyl ether, methyl tert-butyl ether,
methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-
30 diethoxyethane or anisole; nitriles such as acetonitrile, propionitrile, n- or iso-
37
butyronitrile or benzonitrile; amides such as N,N-dimethylformamide, Ν,Νdimethylacetamide, N-methyl formanilide, N-methylpyrrolidone or
hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide or sulfones
such as sulfolane; alcohols such as methanol, ethanol, isopropanol, polyethylene
5 glycols; water or mixtures thereof.